Platform technology for improving ocular drug delivery

Infections with the herpes simplex virus can lead to severe corneal scarring and opacity. The currently available therapy for HSV keratitis involves the use of a 1% trifluorothymidine(TFT) solution. However, one of the major problems associated with TFT therapy is cytotoxicity, which restricts its use in long-term treatment. Due to problems associated with the use of ointments in the eye, acyclovir (ACV) ointment has not been approved for clinical use in HSV keratitis patients in the United States. In addition, ACV ointment is not effective against stromal keratitis or when the deeper ocular tissues are involved, suggesting that ACV has poor permeation characteristics across the corneal epithelium. The corneal epithelium is composed of 5 to 6 layers of columnar epithelium with tight junctions, making paracellular diffusion across this epithelium minimal. Beneath the epithelial layer is the stroma, which contains more than 90% water, and hence presents a barrier to hydrophobic compounds. UMKC researchers have developed esters with sufficient hydrophilicity to be formulated into pharmacologically active compositions, such as aqueous solutions (e.g., eye drops). Compounds of the invention can be effectively transported into the ocular tissues. Specifically, such compounds effectively reach the anterior segment and/or the vitreo-retinal segment when administered either topically or systemically. The compounds formulated have been shown to be effective against viral infections, particularly the herpes group of viruses (e.g., herpes simplex types 1 and 2, varicella zoster virus (VZV) and human cytomegalovirus (HCMV)). The present compounds employ oligopeptide transporters for delivery to the deeper tissues of the cornea. Thus, the present compounds are effective in cases where the corneal stroma and underlying tissues have been infected. These compounds have shown excellent in vitro antiviral activity against HSV 1 in HFF cells and in vivo rabbit epithelial keratitis with no significant cytotoxicity

Both P-gp and MRP2 mediate transport of Lopinavir, a protease inhibitor

Polarized epithelial non-human (canine) cell lines stably transfected with human or murine complementary DNA (cDNA) encoding for various efflux transporters (P-gp/MDR1, MRP1, MRP2, and Bcrp1) were used to study transepithelial transport of Lopinavir (LVR) and compare results with the MDCKII-Wild type cells. These transmembrane proteins cause multidrug resistance by decreasing the total intracellular accumulation of drugs. Lopinavir efflux was directional and was completely inhibited by MK-571, a selective MRP family inhibitor in the MDCKII-MRP2 cell line. Similarly, LVR efflux was also inhibited by P-gp inhibitors P-gp 4008 and GF120918 in the MDCKII-MDR1 cell line. The efflux ratios (Efflux rate/ Influx rate) of LVR in the absence of any efflux inhibitors in the MDCK-Wild type, MDCKII-MDR1, MDCKII-MRP1, MDCKII-MRP2 and MDCKII-Bcrp1 cell monolayers were 1.32, 4.91, 1.26 and 2.89 respectively. The MDCKII-MDR1 and MDCKII-MRP2 cells have significantly increased LVR efflux ratio relative to the parental cells due to the apically directed transport by MDR1 and MRP2 respectively. The efflux ratios in MRP2 and MDR1 transfected cell lines were close to unity in the presence of MK-571 and P-gp 4008 respectively; indicating that LVR efflux by MRP2 and P-gp was completely inhibited by their selective inhibitors. MDCKII-MRP1 cells did not exhibit a significant reduction in the LVR efflux relative to the parental cells, indicating that LVR is not a good substrate for MRP1. Transport studies across MDCKII-Bcrp1 cells indicated that LVR is not transported by Bcrp1 and is not a substrate for this efflux protein. In conclusion, this study presents direct evidence that LVR is effluxed by both P-gp and MRP2 which may contribute to its poor oral bioavailability and limited penetration into the CNS

Translating novel drug delivery techniques to ophthalmic products-unique opportunity for collaboration between academia and pharmaceutical industry

Translational Vision and Neuroscience Research PanelTo improve human health, scientific discoveries must be translated into clinical applications. Such discoveries typically begin at "the bench" with basic research — in which scientists study disease at a molecular or cellular level — then progress to the preclinical arena and ultimately to the patient's "bedside." Translational research has proven to be a powerful process that drives the clinical research engine. A strong collaboration among basic scientists in academia and the pharmaceutical industry is absolutely essential for the development of new ophthalmic products. Instillation of topical eye drops is the preferred and most convenient route of drug administration for treating ocular diseases. However, formulating mits the feasibility of producing aqueous formulation concentrations sufficient water insoluble drugs for topical applications is challenging. Hydrophobicity lio achieve therapeutic levels in the posterior ocular tissues. To overcome these problems, a novel nanomicellar formulation of voclosporin, a calcineurin inhibitor, has been developed to treat dry eye syndrome in association with Lux Biosciences Inc. Moreover this mixed micellar formulation has the ability to deliver the drugs to posterior segment of eye. This formulation underwent Phase I and Phase II trials. This unique nanomicellar drug delivery platform presents potential opportunities for topical administration of additional hydrophobic drugs and the ability to non-invasively target retinal and other posterior segment diseases i.e., age related macular degeneration, diabetic retinopathy, diabetic macular edema and posterior uveitis

COMPARISON OF EXPERIMENTAL AND NUMERICAL TEMPERATURE DISTRIBUTIONS IN TISSUES DURING SHORT PULSE LASER IRRADIATION USING FOCUSED BEAM

ABSTRACT The objective of this work is to perform experimental measurements validated with numerical modeling results for analyzing the temperature distributions and heat affected zone during short pulse laser irradiation of tissues using focused beam. A Q-switched laser is used as a radiation source. A threelayered tissue phantom model of skin consisting of epidermis, dermis, and fatty tissues is first considered for model validation. Tumors are simulated with inhomogeneities embedded inside the tissue phantoms. Experiments are next conducted with freshly excised skin tissue samples from mice and finally on live anaesthetized mice to consider the bulk effect of convective heat transfer due to blood flow. Experimental measurements of axial and radial temperature distributions for all the cases are compared with numerical modeling results obtained using Pennes' bio-heat transfer equation coupled with either traditional Fourier parabolic or non-Fourier hyperbolic heat conduction formulation. Experimentally measured temperature profiles in tissue phantoms, skin tissue samples, and live anaesthetized mice are found to match extremely well with the predictions from the non-Fourier model than the Fourier formulation by considering skin as a multi-layered medium. It is also observed that focused laser beam produces desired temperature rise at the target site with lesser radial spread compared to a collimated laser beam source

Methanolic Extracts of Bitter Melon Inhibit Colon Cancer Stem Cells by Affecting Energy Homeostasis and Autophagy

Bitter melon fruit is recommended in ancient Indian and Chinese medicine for prevention/treatment of diabetes. However its effects on cancer progression are not well understood. Here, we have determined the efficacy of methanolic extracts of bitter melon on colon cancer stem and progenitor cells. Both, whole fruit (BMW) and skin (BMSk) extracts showed significant inhibition of cell proliferation and colony formation, with BMW showing greater efficacy. In addition, the cells were arrested at the S phase of cell cycle. Moreover, BMW induced the cleavage of LC3B but not caspase 3/7, suggesting that the cells were undergoing autophagy and not apoptosis. Further confirmation of autophagy was obtained when western blots showed reduced Bcl-2 and increased Beclin-1, Atg 7 and 12 upon BMW treatment. BMW reduced cellular ATP levels coupled with activation of AMP activated protein kinase; on the other hand, exogenous additions of ATP lead to revival of cell proliferation. Finally, BMW treatment results in a dose-dependent reduction in the number and size of colonospheres. The extracts also decreased the expression of DCLK1 and Lgr5, markers of quiescent, and activated stem cells. Taken together, these results suggest that the extracts of bitter melon can be an effective preventive/therapeutic agent for colon cancer

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Search for supersymmetry in events with one lepton and multiple jets in proton-proton collisions at root s=13 TeV

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